Lysosome-mediated aggregation of galactose-deficient IgA1 with transferrin receptor 1 links to IgA nephropathy

作者：Meijun Si, Jia Fu, Mengting Fang, Yunfei Lu, Junxuan Huang, Hao Li, Peiyi Wang, Maofu Liao, Jian‐Xin Zhu, Pei-yao Li, Wen‐Zhao Zhong, Zhifei Guo, Wei Yang, Zhiming Ye, Hongli Hu, Xueqing Yu · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-60819-w · 被引用次数：8 · 研究领域：Renal Diseases and Glomerulopathies、Complement system in diseases、Erythrocyte Function and Pathophysiology

The retention of galactose-deficient IgA1 (Gd-IgA1) in the mesangium is central to IgA nephropathy (IgAN), but its intracellular fate remains unclear. Here, we show that transferrin receptor 1 (TfR1) mediates Gd-IgA1 uptake into mesangial cell lysosomes, where it forms non-digestible aggregates, disrupts lysosomal function, and triggers inflammatory responses. In renal biopsies from IgAN patients, IgA1 aggregates co-localize with TfR1 within lysosomes. In male mice, TfR1 overexpression enhanced lysosomal accumulation of Gd-IgA1, whereas TfR1 knockdown reduced it. Mechanistically, acidic pH strengthens TfR1–Gd-IgA1 binding via the galactose-deficient hinge region and residue R276. While we acknowledge that sialylation commonly found in patient-derived IgA1 might influence TfR1 binding and that other receptors, such as ASGPR, were not evaluated, our findings nonetheless reveal a lysosome-centered mechanism in IgAN and highlight receptor-mediated retention of Gd-IgA1 as a potential therapeutic target. The retention of galactose-deficient IgA1 (Gd-IgA1) in the mesangium leads to pathogenesis in IgA nephropathy. Here the authors report that Gd-IgA1 is internalized by mesangial cells potentially via transferrin receptor 1, forming aggregates that disrupt lysosomal function and elicit inflammation.